Abstract:

Most studies in this journal describe recent patents. The present study only has one such reference. Instead, we
hope that its contents will trigger investigation of antidepressant drugs along the suggested lines and lead to ensuing patent
applications - first and foremost by more focus on astrocytes. Clinical research has already pointed towards the importance
of these cells, which account for one quarter of brain cortical volume and at least as much of its oxidative metabolism.
Astrocytes express a multitude of receptors, including 5-HT2B receptors. In cultured astrocytes acute treatment with
any of the five SSRIs, fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram, stimulates equipotently and with
sufficient affinity to be therapeutically relevant, the 5-HT2B receptor. Following EGF receptor transactivation and a resultant
autocrine HB-EGF stimulation, these drugs activate two interdependent signal pathways i) the Ras-Raf-Mek-ERK
phosphorylation pathway and ii) the PI3K-AKT-GSK-3β pathway, eventually altering gene expression. Chronic treatment
with fluoxetine upregulates gene expression of cPLA2, ADAR2, GluK2 and 5-HT2B receptors, and RNA editing of the
later two in cultured astrocytes and in astrocytes obtained by fluorescence-activated cell sorting of cells from fluoxetinetreated
mice. Chronic treatment also down-regulates the Gq-protein-coupled receptor-induced increase of intracellular
Ca2+ by inhibiting TRPC function, compromising astrocytic Ca2+ re-filling. This affects glycogenolysis and several steps
in the signal pathways. Since astrocytes in the mature brain and in our cultures do not express SERT, both acute and
chronic effects in cultured astrocytes must be directly mediated by 5-HT2B receptor activation.

Abstract:Most studies in this journal describe recent patents. The present study only has one such reference. Instead, we
hope that its contents will trigger investigation of antidepressant drugs along the suggested lines and lead to ensuing patent
applications - first and foremost by more focus on astrocytes. Clinical research has already pointed towards the importance
of these cells, which account for one quarter of brain cortical volume and at least as much of its oxidative metabolism.
Astrocytes express a multitude of receptors, including 5-HT2B receptors. In cultured astrocytes acute treatment with
any of the five SSRIs, fluoxetine, fluvoxamine, sertraline, paroxetine, and citalopram, stimulates equipotently and with
sufficient affinity to be therapeutically relevant, the 5-HT2B receptor. Following EGF receptor transactivation and a resultant
autocrine HB-EGF stimulation, these drugs activate two interdependent signal pathways i) the Ras-Raf-Mek-ERK
phosphorylation pathway and ii) the PI3K-AKT-GSK-3β pathway, eventually altering gene expression. Chronic treatment
with fluoxetine upregulates gene expression of cPLA2, ADAR2, GluK2 and 5-HT2B receptors, and RNA editing of the
later two in cultured astrocytes and in astrocytes obtained by fluorescence-activated cell sorting of cells from fluoxetinetreated
mice. Chronic treatment also down-regulates the Gq-protein-coupled receptor-induced increase of intracellular
Ca2+ by inhibiting TRPC function, compromising astrocytic Ca2+ re-filling. This affects glycogenolysis and several steps
in the signal pathways. Since astrocytes in the mature brain and in our cultures do not express SERT, both acute and
chronic effects in cultured astrocytes must be directly mediated by 5-HT2B receptor activation.